This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a phase II, randomized, placebo-controlled, double-blinded, multi-center, industry-sponsored trial investigating the use of PF 04494700, an orally bioavailable antagonist of the Receptor for Advanced Glycation End-products (RAGE) as a potential treatment option for patients with mild to moderate Alzheimer's disease. RAGE is known to be involved in the transport of amyloid beta from peripheral to central components, and it is hypothesized that antagonizing the receptor may modulate this transport, resulting in changes of amyloid beta in both plasma and cerebrospinal fluid. In addition, RAGE-ligand has been found to reduce amyloid plaque formation in a murine model, confirming the potential clinical benefit of this as a target in Alzheimer's disease. PF-04494700 has been studied in both preclinical animal and human studies. Its toxicities have been found to include emesis, anorexia, decreased heart rate as well as increased QTc intervals. In single dose phase 1 clinical pharmacokinetic study, dosages of up to 65 mg have been found to be well tolerated. Of note, the mean half-life of this drug in the elderly has been found to be 421 hours, or over 17 days. Also of note is the fact that this drug is a partial inhibitor of the CYP3A4 enzyme, and concomitant use of drugs known to be potent CYP3A4 inhibitors or inducers is restricted in the study. The primary study endpoint is to detect a change in baseline in the Alzheimer's Disease Assessment Scale Cognitive measure (ADAS-cog) after 18 months of treatment with this new agent. This study will randomize patients to a high dose, a low dose, or placebo, with treatment lasting 18 months. Secondary objectives of this study include evaluating the dose response of treatment with this new drug relative to placebo, evaluating the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of drug to potential biomarkers, and relevant efficacy and safety endpoints. Eligible patients are those with mild to moderate Alzheimer's disease. Randomization is a 1:1:1, and an expected 399 participants will be enrolled. At the GCRC at Georgetown, 10 patients are expected to be enrolled.